Fertility Drugs and Selective Reduction

Joni Payne, Cindy Crissman, Jeri
Crenshaw, Kelly Hagan

According to the National Center for Health Statistics there are 2.3
million childless couples in the United States due to infertility. Infertility
is defined as 12 months of unprotected intercourse without pregnancy. There
are two types of infertility. Primary, which indicates that the woman has
never been able to get pregnant and secondary, which indicates that the
woman has had at least one other child previously.

Approximately one third of the infertile couples in the United States
are appropriate candidates for the Assisted Reproductive Technologies (ART).
These are procedures which involve high technology and the combination
of sperm and eggs to treat infertility. There are 5 types of ART, Intrauterine
Insemination (IUI), In Vitro Fertilization (IVF), Gamete Intrafallopian
Transfer (GIFT), Zygote Intrafallopian Transfer (ZIFT), and Intracytoplasmic
Sperm Injection (ICSI).

Intrauterine insemination is the most common form of artificial insemination.
A syringe is used to inject the sperm into the cervical canal right before
or on the day of ovulation. Used for men with low sperm count, poor sperm
quality, overly dense semen or any other problem that prevents the male
from having intercourse.

For the process of in vitro fertilization a women's ovaries are first
stimulated with fertility drugs to produce several usable eggs. Then the
eggs are retrieved from the ovaries using an ultrasound guided needle.
The eggs are fertilized in a petri dish and then the embryo is placed in
the mother's uterus. IVF is useful for women who have absent or diseased
fallopian tubes, which is where normal fertilization occurs, women who
have uncurable endometriosis, and unexplained infertility that has not
responded to other treatments, also possibly a male contributing factor.

Gamete intrafallopian transfer which is similar to IVF but the women
must have at least one functioning fallopian tube and no suggestion of
a male factor involved. The procedure is the same up to egg retrieval,
3-5 eggs are taken from the ovaries and then are placed in the fallopian
tube with the husband's sperm, and allowed to fertilize naturally. GIFT
was developed to more closely simulate the natural process of fertilization.
GIFT is recommended for couples with unexplained infertility, or when infertility
is due to cervical or immunological factors.

Zygote intrafallopian transfer again is similar to IVF again but this
time a fertilized egg is place in the fallopian tube. ZIFT is performed
in cases where the woman has normal fallopian tubes but there is a sever
male factor of infertility. ZIFT became available in 1993.

Intracytoplasmic sperm injection is the newest treatment for severe
cases of male infertility. This treatment was first used in 1994 at Univ.
Cal at San Fran., the baby was born in Feb 1995. Again the woman must use
fertility drugs to stimulate egg production. The eggs are then aspirated
through the vagina using vaginal ultrasound. Then the male provides a semen
sample, which is prepared by centrifuge to separate the live sperm from
any debris or dead sperm. One single live sperm is picked up by a glass
needle and injected directly into an egg. Fertilization rates are 70-80%
of all eggs injected according to UCSF. They also say that worldwide the
rate of birth defects in pregnancies using ICSI are no higher than those
seen in the general population. (Genesis)

There are several drugs used to treat infertility. First is Lupron which
is a gonadotropin releasing hormone (GnRH) agonist. GnRH is produced by
the hypothalamus. GnRH stimulates the pituitary to produce Luteinizing
hormone (LH) and Follicle stimulating hormone (FSH). FSH in females is
responsible for the development and maturation of ovarian follicles. In
males FSH is responsible for the development and maturation of sperm. In
females a surge of LH will initiate ovulation. LH in males initiates and
maintains testicular production of testosterone.

Lupron is a subcutaneous injection given in the thigh at approximately
the same time each day. The purpose of Lupron is to prevent premature LH
surge and ovulation. Lupron is used in conjunction with other fertility
drugs mainly Pergonal which will be discussed later. Lupron is usually
given 7-10 days prior to initiating another fertility drug.

Some women experience temporary fluctuations in mood, hot flashes, nausea,
and symptoms not vastly dissimilar form PMS. No serious long lasting side
effects have been reported. (Pacific)

Next is Serophene also know as Clomid. This drug is often referred to
as the "fertility pill". It is used to treat infertile women who have an
ovulation problem. It works by helping your pituitary gland improve the
stimulation of developing eggs in the ovaries. These drugs may not help
a woman become more fertile if she is already ovulating normally. 60-80%
of women treated with Serophene or Clomid will ovulate normally. Only half
of those patients who ovulate will become pregnant. 10-20% of women taking
Serophene or Clomid will experience side effects, which include hot flashes,
blurred vision, nausea, bloating sensation and headache. (Atlanta) Due
to the visual problems patients should be advised that driving or operating
machinery may be dangerous especially in conditions of variable lighting.
Serious side effects are rarely seen with these drugs, but there are two
that warrant discussion. First there is a possibility of multiple pregnancy.
With 10% of women taking the drug having twins, 1 in 400 having triplets
and 1 in 800 having quadruplets. (Atlanta) Also these drugs may cause ovarian
cysts and usually will resolve without treatment. But on occasion the women's
ovary has been removed due to complications. Studies have shown that if
pregnancy does occur due to the use of these drugs there is not an increased
risk of miscarriage or congenital birth defects when compared to other
infertile couple who conceived without Clomid or Serophene.

Clomid or Serophene should not be given to patients with liver disease.
In cases of abnormal or irregular uterine bleeding, abnormalities of the
endometrium or cervix should first be ruled out. If the patient already
has ovarian cysts these drugs should not be given. 4 to 6 cycles of treatment
are necessary before one has given Clomid or Serophene an adequate trial.
(Atlanta)

Next are Pergonal and Metrodin these two are naturally occurring hormones
excreted in the urine of post-menopausal women. When given to pre-menopausal
women these hormones stimulate ovarian follicle formation and maturation
with associated egg production. For actual ovulation to occur a separate
injection of HCG (human chorionic gonadotropin) is needed to provide the
surge of LH, which will release the egg. Pergonal or Metrodin are usually
given for 7-12 days, per cycle.

Complications and side effects are hyperstimulation of the ovary, possible
increased ovulation with multiple gestations and possible premature delivery
or pregnancy loss. Hyperstimulation of the ovaries consists of low abdominal
pain, pressure, weight gain and swelling. With avoidance of activities
and pelvis rest, meaning no intercourse these symptoms usually resolve
spontaneously. Although an occasional patient has needed to be hospitalized
for observation and fluid hydration. (Bay)

The incidence of multiple gestations appears to be 20-40%, most of these
are twins 75%, triplets or more account for 25%. 60-80% of the pregnancies
are one fetus. (Bay)

Medical studies indicate that 70-100% of women ovulate following Pergonal
or Metrodin. The conception rate is reported to be 15-50% with 25% incidence
of miscarriage. Somewhat higher than the 15% miscarriage rate seen in the
general population. (Bay)

Lastly Gonal F/ Follistim Gonadotropins are drugs used for ovulation
induction for women who don't ovulate on their own, or who need multiple
eggs for an insemination process. These drugs are a more pure form of FSH.
These are obtained from recombinant technology not from the urine of menopausal
women. Another plus is that these injections are with a much smaller needle
so it would be easier for the pt. to give the shot to themselves.

Once again when given to pre-menopausal women the hormone stimulates
ovarian follicle formation and maturation, with assoc. egg production.
An injection of HCG is needed for the LH surge so actual ovulation can
occur. Again 7-12 days of injections is the typical regimen.

Complications and side effects resulting in the use of these drugs are
related to hyperstimulation of the ovary, possible increased ovulation
with multiple gestations and possible premature delivery. Again with avoidance
of activities and pelvic rest these symptoms usually resolve spontaneously.
(Bay)

Studies indicate that 70-100% of women ovulate with these drugs and
the conception rate is 15-20% with 25% having miscarriages. again the normal
rate of miscarriages for the general pop is 15%. (Bay)

These next two drugs are not specifically for fertility but as supplemental
drugs that would aid in the fertility process. Birth control pills are
sometimes used for suppression of the ovaries prior to a stimulated cycle.
Common side effects include headaches, weight gain, light periods, mid-cycle
spotting and elevated blood pressure. A drug named Provera is used to induce
a period when there is no natural cycle. side effects are bloating, headaches,
mood swings, swelling of face and extremities, increase blood pressure
and weight gain.

There is much cost associated with fertility drugs, both physical and
financial. The goal of fertility medicine is to produce a single healthy
baby. The injectable drugs increase the number of eggs a woman produces,
the chance of multiple fetuses also increases. Doctors cannot precisely
control how many fetuses will result. In cases involving injectable fertility,
about 15 percent of the pregnancies result in multiple births compared
to 1 percent without the drugs. (Smith) Fertility drugs are given to stimulate
the ovaries to produce 5 or 6 eggs. These drugs can also cause overstimulation
where 34 eggs can ripen at once. This stress on a woman's system can lead
to kidney failure. In 1993 alone, 171 women were hospitalized with this
potentially life threatening condition. (Kong)

A reproductive endocrinologist (RE) completes the same training and
residency as an OB/GYN, but spends and addition 2 years in a fertility
fellowship. Doctors listed as "infertility specialists" in HMO directories
or in the phone book are not necessarily reproductive endocrinologists.

Lupron is a member of a class of drugs known as gonadotropin releasing
hormone. It is FDA approved to alleviate bone pain and some urinary problems
that are associated with metastatic prostate cancer. Many women are given
Lupron during fertility treatment without being told that the drug does
not have FDA approval for that use. (Kong) This drug can also cause birth
defects, if present during pregnancy.

Ovulation inducing agents have been available for clinical use for approximately
30 years. With the advent of modern assisted reproductive technologies,
their use has escalated dramatically in recent years. A major risk that
has received much publicity recently is that these ovulation-inducing drugs
may increase the risk of developing ovarian cancers. There is still no
definite answer to this question because there is data in support of an
association between fertility drugs and ovarian cancer, but there is also
equally convincing data that there is no such association. One study suggests
that women who use fertility drugs are 3 times more likely to develop ovarian
cancer. (Benjamin) Another more recent study suggests that it is infertility
not the infertility drugs that cause in increase in the risk of ovarian
cancer. "While ovarian cancer accounts for only 4% of all cancers in women,
it is a particularly dangerous form of cancer. Less than half of all women
with ovarian cancer survive beyond 5 years of being diagnosed." (La Voie)
The FDA has begun to request that drug firms add the potential risk of
ovarian cancer to the adverse drug reaction section of fertility drug labels.
the possibility that the use of fertility may increase the risk of ovarian
cancer has prompted researchers to conduct studies to determine the long-term
effect of such drugs.

According to the National Center of Health Statistics, the number of
triplets has more than tripled since the 1970's and the use of fertility
drugs accounts for most of the increase. Multiple pregnancies virtually
always end with premature delivery. this increases the chance of losing
all the babies or delivering ones that are permanently damaged, blindness
or death. On the average, triplets stay in intensive care for four to six
weeks. Accommodating multiple births, as well as other high-risk births
can be a challenge to any hospital. Caring for infants once home can be
a struggle for new parents, especially if the need for special medical
attention exists. (Rosenthal)

Other than physical costs, there are also financial costs to consider.
Fertility treatments are very expensive. Some couples do not have insurance
and must pay for the cost entirely on their own. Overall, about 25% of
traditional insurance plans and 37% of HMO's offer coverage for infertility
treatments. (Kiplinger) It is now mandatory in 11 states that health insurance
coverage includes infertility. Kentucky is not one of them. Some insurance
policies cover only certain costs, so it may dictate what types of treatment
you receive.

One frequently used drug in Metrodin. Metrodin is given by daily injection,
over the course of 9 to 12 days. A $200 per dose, the cost can reach $1900
per cycle. (Minch) The cost of these drugs has caused some to seek out
pharmacies in Mexico. Internet postings brag about the savings to be had
by purchasing the drugs overseas. It is legal to bring medication across
the border, as long as you have a prescription and bring back no more than
the amount prescribed. Many patients mail order Perganol from other countries
where they are far cheaper than the US. For three cycles of Perganol, the
cost in the US is $4,000. In Mexico, the cost is $780. (Kiplinger)

One couple, whose attempts were unsuccessful, was quoted as saying,
"With an adoption, when you pay $10,000 you are sure to get a child, but
with infertility treatments, you pay your $10,000 but you are not sure
of any thing." (Kiplinger) Many couples would agree that the cost is worth
it, that they are willing to forgo a new home or car or expensive vacation.

Fertility treatments can also bring about other controversial issues,
such as is the case with selective reduction. Selective reduction is a
process used to reduce the number of developing fetuses in the case of
a multiple pregnancy. It is performed to improve the chances for survival
of the remaining fetuses. Though, selective reduction has been performed
on women with naturally occurring multiple pregnancies, the majority are
used to reduce the number resulting from fertility drugs, in-vitro fertilization,
and other reproductive techniques.

There are many procedures used to go about selective reduction but the
most common technique involves injecting potassium chloride into the heart
of each fetus to be eliminated (MacIsaac, 3). Other techniques are transcervical
suction, transabdominal and vaginal needling of the heart, exsanquinating,
which means the forcible expulsion of blood from a part of the body usually
the heart, and air injection. Except for transcervical suction, these techniques
target the developing heart of the fetus because once the heart is destroyed
the fetus immediately dies.

Selective reduction is usually performed as soon as possible because
the longer the mother carries the multiple fetuses the greater the negative
consequences on the remaining fetuses. Most reductions occur between the
ninth and thirteenth weeks of pregnancy (MacIsaac, 3). These usually involve
elimination of the fetuses that are most easily accessible to the needle
or other device rather than which ones are the most viable (Streeter, 1).
Reductions occurring in the eighteenth to twenty-fourth week are based
more on the elimination of weak or abnormal fetuses. At all times, though,
doctors try to eliminate the weak or abnormal fetuses but since it sometimes
takes awhile for abnormalities to show, many fetuses may appear equally
viable well into the pregnancy.

Statistically speaking, selective reduction does not appear to be simply
a matter of convenience but of necessity. Thirteen percent of multiple
pregnancies result in no live births if selective reduction is not performed
and 15.5 % result in premature births (MacIsaac, 4). The remaining 71.5%
represents either pregnancies where selective reduction was used or full
term births. However, in the full term births as well as the premature
births, the majority did not result in the survival of all babies. Also,
many of the surviving children of full term multiple pregnancies suffered
various problems such as cerebral palsy, mental retardation and blindness.

The obvious controversy surrounding selective reduction is that some
feel it is a form of abortion. Many pro-lifers feel that the termination
of "life" is unjustifiable even if the process will increase the chances
of survival of the remaining fetuses. One pro-life supporter, Shelley Lembke,
stated in an article of Totally Catholic E-Zine that the correct term for
selective reductions should be selective "abortions". She felt that the
one fetus was being deemed more important than the other. Stacy, a women
who with the aid of fertility drugs conceived 10 children and had to undergo
selective reduction to ensure her own survival as well as that of the fetuses,
disagrees. She says, "This is not abortion. When a woman gets an abortion,
she does not want to have a child. Someone goes through this because they
desperately want to have a child" (Peyser, 2). Another pro-life supporter
cited an incident that occurred in England where a woman who could not
afford twins opted to have one fetus removed as evidence of the wrongs
of selective reduction. This account, however, is unusual for two reasons:
1) selective reductions are usually performed either to ensure the health
of the mother or fetuses not due to expected financial hardships and 2)
twins develop within the same sac in the womb and the attempt to eliminate
one will most likely harm the other. This is not a problem in multiple
pregnancies resulting from artificial means because the fetuses develop
in separate sacs so it's easier to eliminate some without harming the others.
Another controversial issue with selective reduction is that it's viewed
as a way of correcting the mistakes of reproductive technology after the
fact rather than correcting the technology itself. As food for thought,
a New York Post article asked the question: If technology creates a multiple
pregnancy -an event Mother Nature usually rejects-does it then make sense,
medically or morally, to let nature decide the outcome?" (Peyser, 1)

Clinics are ever increasing the incidences for selective reductions.
The chance for successful implantation by transferring two embryos is 15-20%,
with three it rises to 20-25%, and so on until the percentages top out
with the transfer of six embyos giving successful implantation rates of
nearly 40 percent. As clinics compete to boost success rates, some have
been transferring more and more embryos in a cycle--not the usual two or
three, but as many as eight--to increase the odds of pregnancy. There's
no limit to the number of embryos a clinic can transfer into a woman's
uterus.

Multiple births are risky for mothers and babies. Twins are seven times
more likely to be born smaller than single infants. More than half of all
twins weigh less than five and a half pounds, compared to six percent of
single babies, and four out of every 100 twins die. The risk of low birth
weight and death only increases with multiple births. For example, more
than 90 percent of triplets born each year weigh less than five and a half
pounds and ten out of every 100 die.

Despite these risks, the rate of multiple births increased twenty-four
percent between 1983 and 1993 with 2.5 percent of all 1993 babies born
as twins, triplets, quadruplets, or quintuplets. The arate of premature
births climbed nearly 15 percent. In 1993, the most recent year tabulated,
babies born weighing 5.5 pounds or less accounted for 7.2 percent of all
births--the highest low birthweight rate since 1976. Thus, the rise in
multiple births show a direct correlation with the rise in low birhtweight
babies.

While newnatal intensive care continues to save many of these tiny babies,
some public health specialists worry that if the trend continues, their
numbers could drive up pre- and post-natalmedical costs and perhaps the
infant mortality rate.

Because of these risks, some clinics (nearly 300 in the U.S.) perform
selective reductions on unborn fetuses. While there are many advantages
to performing these selective reductions, the main one being to increase
the birth weight and chance of survival of existing fetuses, there are
also risks associated. These risks of selective reduction, termed by some
of its opponents as selective feticide, include: the accidental loss of
pregnancy, the performance of the procedure on the wrong 'healthy' fetuses,
chorioamnionitis (inflammation of the tissues surrounding the fetus), premature
dilivery, and permanent damage of the surviving fetuses. There is also
some question of the psychological effects of selective reduction on the
mother, and it has been proven that severe depression can persist after
the procedure. Many consider the selective reduction procedure to be an
abortive process and deem it morally and ethically wrong for the same reasons.

Selective reduction procedures, as well as the many Assisted Reproductive
Technologies aforementioned, are not currently under governmental regulation.
To date, there is no significant legislation regulating the action of fertility
clinics or the use of fertility drugs. Many organizations including the
Ethics Advisory Board of the U.S. Department of Health Education and Welfare,
the American Society for Reproductive Medicine, the American College of
Obstetricians and Gynecologists, and the Judicial Council of the American
Medical Association are convening in an attempt to establish guidelines
that clarify the responsibilities of participants and set professional
standards. However, agreements have yet to be made upon such restriction.

The technology associated with fertility treatments has moved at such
a rapid pace that legislation has not been able to keep up. It is growing
more and more important to seriously examine the moral and ethical issues
involved in such manipulations in order to have the tools to approach situations
such as the following:

A plane crash cuts short the lives of an infertile couple, leaving two
frozen embryos orphaned. Do the embryos have a right to be born? If so,
do they inherit the couple's estate? Who would have decision-making powers
over the fate of the embryos?

Infertility

Defined as 12 months of unprotected
intercourse without pregnancy.

Two types: Primary Infertility - meaning
pregnancy has never occurred.

Secondary Infertility - meaning there
has been one or more pregnancies previously.

Assisted Reproductive Technologies
(ART)

Procedures that involve high technology
and the combination of sperm and eggs to treat infertility

5 Types of Assisted Reproductive
Technologies

1) Intrauterine Insemination (IUI)

2) In vitro Fertilization (IVF)

3) Gamete Intrafallopian Transfer
(GIFT)

4) Zygote Intrafallopian Transfer
(ZIFT)

5) Intracytoplasmic Sperm Injection
(ICSI)

Fertility Drugs

4 Types: Lupron

Serophene or Clomid

Pergonal or Metrodin

Gonal F or Follistim Gonadotropins

Supplemental Drugs

Birth Control Pills

Provera

Common Side Effects:

Hot flashes

Nausea

Mood Swings

Blurred Vision

Bloating

Headache

The basic question is: To what
extent should technology be allowed to alter the normal course of nature?
In other words, where does it all end?

The following three examples illustrate
the kinds of moral and ethical questions the laboratory director of a major
IVF program encounters:

A 28-year-old female medical student
asked:

Is it possible for you to freeze two
or three stimulated cycles of my eggs now? I'll be over 35 by the time
I get out of medical school, and I'd like to begin my family about age
40 but with age-28 eggs.

When a graduate student received widespread
publicity after the birth of identical twin calves from a cow embryo he
had split, a couple inquired of the laboratory director:

Would you please split one of our
embryos so we can have identical twins?

And a terminally ill man asked:

My wife has agreed to bear me a large
family after I'm gone. Would you freeze several samples of my sperm and
artificially inseminate her over the years so she could have my family?

Professor Arthur Caplan, medical
ethicist:

"We've got couples who are using
surrogates, bought egg, bought sperm, and creating children. We have a
case in California where they've gotten divorced in the middle of all this,
and the legal system is trying to figure out who is the parent of this
baby. Again, situations where people have had babies after deaths, sperm
being removed now surgically, and even though the person is dead, someone
else might want to have a child that way.

We really as a society have this wonderful
technology. It's great. It can help infertile people have kids, and I don't
think anybody can argue with that. But we've got no ground rules, not even
minimal limits, just to say standardize the informed consent, the information
that people get, and maybe let's put some restrictions on who can use this
technology. For example, do you have to be infertile to use it? what if
I just wanted as a woman to make seven babies just because I wanted to
be a celebrity? Right now, there's nothing to stop that.

...the fact is we've been going at
this technology now for 20 years, and we don't have any consensus, even
minimal regulation out there. What I'm afraid of is that as people see
the technology moving seven babies here, people who are dead having children,
babies by design, ordering embryos from overseas or even for eugenic reasons,
saying I want a tall baby, we're going to find ourselves with a technology
that's going to get a backlash, and people who might benefit won't, because
we haven't put even minimal rules in place to govern it."

Evaluation

Two words kept reappearing in the evaluations made by the class--informative
and interesting. The class as a whole felt the presentation was well-prepared
and organized. It was commented that the presentation "hit all the major
points" and that it "tied into medical ethical issues." Most were impressed
with the use of the overheads. Many commented that the presentation was
well-researched and very thorough. A few expressed their liking of the
frequently asked questions and were impressed with the way that it focused
on regulations.

Many said that they would have liked to have asked questions. A couple
of people did not like presenters reading directly from the notes, but
one admitted that it would be "difficult not to with the extent of the
info presented."